Chronic stress early in life (ES), including neglect, abuse, loss of parent and severe poverty, affects the majority of the world's children (UNESCO report, 2004). This is of major clinical importance because chronic childhood stress is associated with cognitive (and psychiatric) disorders later in life. Because elimination of global ES is not feasible, effective therapies that can be given post hoc to prevent the effects of ES on mid- life cognitive decline are necessary. Having defined a rodent model of ES which results in enduring deficits of hippocampus-dependent cognitive function and LTP, together with dendritic atrophy, we found that post hoc blocking of the receptor (CRFR1) of the stress-activated neuropeptide, corticotropin releasing hormone (CRH) immediately after the ES period, abrogated these deficits. Whereas these data are encouraging, major gaps in our knowledge require study in order to translate these experimental findings into therapies for children. In this revised continuation proposal, we propose (1) to test if pathological activation of central or of peripheral CRFR1 is responsible for ES-provoked learning and memory defects and dendritic atrophy; (2) to distinguish between the hypothesis that ES leads to enduring changes in hippocampal structure and function that are irreversible after a critical period of development, and the possibility that ES initiates hippocampal derangements that progress throughout life. In the latter case, therapeutic interventions in young adult ES graduates will still prevent the cognitive and structural deficits; (3) Because the structural changes provoked by ES-dendritic atrophy and synapse/spine loss--underlie the cognitive deficits, the mechanisms of dendritic atrophy will be studied, focusing on the role of hippocampal CRH-CRFR1 signaling; (4) Because dendritic atrophy derives from chronic loss of dendritic spines, the mechanisms by which stress, via CRFR1 activation, provokes dendritic spine collapse will be examined. The proposed studies, spanning in vivo and in vitro systems, will provide insight into the mechanisms by which ES impacts neuronal integrity, synaptic plasticity and cognitive function long-term. Because ES affects the majority of the world's children, these studies address a problem of paramount importance, which is strikingly understudied. The proposed studies will identify a novel mechanism, CRH-CRFR1 signaling, as pivotal in the disturbances provoked by ES. Because the proposed studies will demonstrate the potential for post hoc intervention, and because compounds targeting CRFR1 are under clinical development, the results of these studies have tremendous translational potential. PUBLIC HEALTH RELEVANCE: This project studies how chronic stress early in life impacts our brain. The United Nations has found that more than half of the world's young children grow up under chronic stress (e.g., hunger, war, loss of parent). It is also known that early-life stress is associated with impairments of memory and other cognitive functions subserved by the brain's hippocampus region, and that these deficits persist during adulthood and worsen with age. We plan to test the possibility that a brain-specific stress hormone (CRH) contributes in a major way to the adverse, long-lasting effects of early stress on memory during adulthood and middle-age, and find out how this happens. Our studies will identify new therapies (blocking the actions of CRH) for prevention and/or reversal of the severe impact of early stress on cognitive function- a major advancement in world health.